"Tumor cell Hypoxia as a Factor in Cancer Therapy" is a long range project aimed at promoting a more quantitative analysis of the effects of therapeutic perturbations on the dynamics of neoplastic growth. Using a variety of in vivo and in vitro assay procedures (spleen colony assay, serial dilution assay, I125-iododeoxyuridine pre-labelling technique, in vitro colony assay, etc.) an attempt will be made to evaluate the importance of the oxygen effect in radiation therapy and to devise treatment regimens designed to reduce or eliminate the survival advantage of hypoxic tumor cells. Specifically, the effect of simultaneous and sequential administration of hyperthermia and chemical radiosensitizers (electron-affinic agents) on the radiation response of euoxic and hypoxic tumor cells as well as on normal body tissues (bone marrow, skin, intestine) will be investigated. We have previously demonstrated that exposure of tumors to physiologically tolerable doses of nitroimidazoles or hyperthermia produces only modest radiosensitization (dose modifying factor of up to 2.0). However, combined administration of hyperthermia and nitroimidazoles induces very pronounced, synergistic radiosensitization effects with dose modifying factors of 4.3 or higher. This DMF is considerably better than the 3-fold sensitization that could be achieved by full oxygenation of previously hypoxic tumors. Since identical combination treatment produces only modest or no radiosensitization in normal body tissues, the proposed treatment regimen could produce a large therapeutic gain factor in cancer radiation therapy. Our immediate goal is to further investigate the cellular and molecular mechanisms responsible for synergistic radiosensitization, to evaluate the mechanisms responsible for direct cytocidal effects of hyperthermia and electron-affinic agents, and to obtain additional information on environmental and intracellular factors which govern the magnitude of these effects. We also plan to extend this work to newly synthesized electron-affinic agents, to optimize in vivo treatment strategies and modify biological variables (such as tumor pH) in living animals to determine whether such manipulations could further increase radiosensitization of hypoxic tumors without causing undesirable side effects on normal tissues of the host.